The present invention relates to a novel class of substituted indane or dihydroindole compounds having effect at dopamine D4 receptors. The compounds are selective dopamine D4 ligands or they have combined effects at dopamine D4, 5-HT receptors and/or the 5-HT transporter. These compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, including psychosis, depression and anxiety.
Compounds related to the compounds of the present invention are known from DE patent application No. 4414113 describing certain 4-(indol-3-yl)-1-(indol-3-yl-alkylene)-piperidines. The compounds herein are claimed to show serotonin antagonistic and agonistic activities and to have effect on DOPA-accumulation in striatum. No biological data are given.
GB patent application No. 2 044 254 describes certain 1-(indol-3-yl-alkylene)-piperidine derivatives which are substituted in position 3 or 4 of the piperidine ring with an isoindole, or an isoquinoline ring. These compounds are claimed to have 5-HT reuptake inhibiting activity and to be useful as antidepressants.
Furthermore, in WO patent publications No. WO 9421627, WO 9421630 and WO 94 21626 various series of indolyl- or indazolylmethyl piperidine or piperazine derivatives are described to be selective dopamine D4 antagonists. No data are given. The compounds are only said to give Ki values of less than 1.5 xcexcM in a test for displacement of 3H spiperone from human dopamine D4 receptor subtypes in clonal cell lines.
WO patent publication No. 95/33721 relates to 1-(indanemethyl, dihydrobenzofuranylmethyl, or dihydrobenzothiophenylmethyl)piperidine, -tetrahydropyridine, or piperazine derivatives. The 1-indanemethyl compounds disclosed herein are substituted in position 6 with an amino containing group. The compounds interact with central 5-HT receptors, in particular with 5-HT1A and 5-HT2A receptors. Some of the compounds are said to have 5-HT reuptake inhibiting effect.
Dopamine D4 receptors belong to the dopamine D2 receptor family which is considered to be responsible for the antipsychotic effects of neuroleptics. Dopamine D4 receptors are primarily located in areas of the brain other than striatum (Van Tol, et al. Nature, 1991, 350, 610). The low level of D4 receptors in striatum suggesting that compounds which are selective for the dopamine D4 receptor will be devoid of extrapyramidal activity, is illustrated by the antipsychotic clozapine which has a high affinity for dopamine D4 receptors and is lacking extrapyramidal side effects, (Van Tol, et al. Nature, 1991, 350, 610). Also, dopamine D4 receptor levels have been reported to be elevated in schizophrenic patients (Seeman et al., Nature, 1993, 365, 441.).
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have e.g. been reported:
Antidepressive effect and improvement of the sleep quality (Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) reduction of the negative symptoms of schizophrenia and of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5, 33). Finally, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; xe2x80x9cMigrainexe2x80x94Current trends in research and treatmentxe2x80x9d; PJB Publications Ltd.; May 1991).
Clinical studies have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT1A partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds may be useful in the treatment of aggression (Sanchxc3xa9z et al., Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A ligands have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol.andToxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147;and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol.Biochem. and Behav. 1994, 47, 509-513) suggesting that 5-HT1A agonists are useful in the treatment of extrapyramidal side-effects induced by conventional antipsychotic agents such as haloperidol.
5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
5-HT reuptake inhibitors are well known antidepressant drugs.
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of psychoses and positive symptoms of schizophrenia and compounds with combined effects at dopamine D4 and 5-HT receptors and/or the 5-HT transporter may have the further benefit of improved effect on other psychiatric symptoms in schizophrenic patients such as depressive and anxiety symptoms. 5-HT1A and 5-HT2A receptor ligands and 5-HT reuptake inhibitors have different activities in different animal models predictive of anxiolytic and antiaggressive effects (Perregaard et al., Recent Developments in Anxiolytics. Current Opinion in Therapeutic Patents 1993, 1, 101-128) and/or in models predictive of effects in other psychic disorders and it is considered highly beneficial to have such combined serotonergic effects.
Compounds with dopamine D4 receptor activity combined with effect at 5-HT receptors and compounds with dopamine D4 receptor activity combined with 5-HT reuptake inhibiting effect is considered a new therapeutic approach in the treatment of neurologic and psychiatric disorders, including in particular psychosis.
The object of the present invention is to provide compounds with dopamine D4 activities or with combined effects at dopamine D4 receptors, 5-HT receptors and/or the 5-HT transporter.
It has now been found that certain substituted indane or dihydroindole compounds have effect at dopamine D4 receptors. Additionally, many of the compounds interact with central serotonergic receptors, in particular with the 5-HT1A and/or the 5-HT2A receptors and/or they act as 5-HT reuptake inhibitors.
Accordingly, the present invention relates to novel compounds of the formula I 
wherein A is a group 
Y is a hydrocarbon group completing an indane ring, a group NR1 completing a dihydroindole ring, or a group N completing a dihydroindole ring linked via the 1-position;
W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;
W is CO, SO, or SO2, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6; or
W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6, and if Y is N completing a dihydroindole ring attached via the 1-position then m is 2, or 3; and if Y is NR1 completing a dihydroindole ring linked via the 2-position then m is 1, 2, or 3; the dotted line, emanating from X, indicates an optional bond; when it does not indicate a bond, X is N, CH or COH; and when it indicates a bond, X is C;
R1 is
hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl, heteroaryl, aryl-C1-6alkyl, heteroaryl-C1-6-alkyl, acyl, thioacyl, C1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl, or heteroarylsulfonyl
R15VCOxe2x80x94 wherein V is O or S and R15 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl, or heteroaryl; or
a group R16R17NCOxe2x80x94 or R16R17NCSxe2x80x94 wherein R16 and R17 are independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, heteroaryl, or aryl, or R16 and R17 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepin group;
R2-R5 are independently selected from hydrogen, halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 alk(en/yn)yl, C1-6-alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C1-6 alkylsulfonyl, one of R2-R5 alternatively being a group xe2x80x94NR13R14 wherein R13 is as defined for R1 and R14 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 alk(en)yn)yl, aryl, heteroaryl, aryl-C1-6 alkyl, or heteroaryl-C1-6-alkyl, or
R13 and R14 together with the N-atom to which they are linked form a group 
xe2x80x83wherein Q is Cxe2x95x90O, Cxe2x95x90S or CH2; T is NH, N-alkyl, S, O or CH2; and p is 1-4, inclusive; or two adjacent groups taken from R2-R5 may be joined and designate xe2x80x94(CH2)3xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94, thereby forming a fused 5 membered ring;
R6-R9 and R11-R12 are independently hydrogen, halogen, cyano, nitro, C1-6-alk(en/yn)yl. C1-6-alkoxy, C1-6-alkylthio, hydroxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 alk(en/yn)yl, aryl, heteroaryl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, or C1-6 alkylsulfonyl, or two adjacent groups taken from R6-R9 may together form a methylenedioxy group;
R10 is as defined for R1 above;
with the proviso that the substituent R3 or R4 in position 6 may not be xe2x80x94NR13R14 when Y is CH2, W is a bond, n+m is 1 and the ring is linked via the 1-position; or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the invention have been found to show high affinity for dopamine D4 receptors and some of the compounds have been found also to show affinity for serotonergic receptors including 5-HT1A receptors and/or for 5-HT2A receptors. An important group of compounds according to the invention are the compounds which have effect at dopamine D4 receptors combined with 5-HT reuptake inhibiting effect.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep.
In another aspect of the present invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect the present invention provides the use of a compound of Formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
Some of the compounds of general Formula I exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The expression C1-6-alk(en/yn)yl means C1-6-alkyl, C2-6-alkenyl, or C2-6-alkyl group.
The expression C3-8-cycloalk(en)yl means a C3-8-cycloalkyl group, or a C3-8-cycloalkenyl group.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
The terms C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylamino, C1-6 alkylcarbonyl, etc. designate such groups in which the alkyl group is C1-6 alkyl as defined above.
The term C3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term C3-8 cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and containing one double bond.
The term aryl refers to a carbocyclic aromatic group, such as phenyl, naphthyl, in particular phenyl, including methyl substituted naphthyl, or phenyl.
The term heteroaryl refers to a mono- or bicyclic heterocyclic group such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, in particular pyrimidyl, indolyl, and thienyl.
Halogen means fluoro, chloro, bromo or iodo.
As used herein the term acyl refers to a formyl, C1-6 alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C1-6alk(en/yn)ylcarbonyl, C3-8-cycloalk(en)ylcarbonyl, or a C3-8-cycloalk(en)yl-C1-6alk(en/yn)ylcarbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
One group of compounds according to the invention are the compounds wherein Y is completing an indane ring.
Other groups of compounds according to the invention are the groups of compounds wherein Y is NR1 or N completing a dihydroindole ring.
Accordingly, one group of compounds are the compounds wherein Y is CH2 and A is a group a) linked to X via the 2 or the 3 position, or a group b), in particular a group a).
Another group of compounds are the compounds wherein Y is CH2 and A is a group group c) linked to X via the 4, 5, 6, or 7 position.
A third and fourth group of compounds are the compounds wherein Y is NR1 or N and A is a group a) linked to X via the 2 or the 3 position, or a group b), in particular a group a).
A fifth and sixth group of compounds are the compounds wherein Y is NR1 or N and A is a group c) linked to X via the 4, 5, 6, or 7 position.
Particular embodiments of the present invention are compounds wherein Y is a hydrocarbon group completing an indane ring and
linked via the 2 position and A is a group a) which is linked via position 3;
linked via the 2 position and A is a group a) which is linked via position 2;
linked via the 2 position and A is a group b);
linked via the 2 position A is a group c) which is linked via position 4, 5, 6, or 7;
linked via the 1 position A is a group a) which is linked via position 3;
linked via the 1 position and A is a group a) which is linked via position 2;
linked via the 1 position A is a group b); or
linked via the 1 position and A is a group c) which is linked via position 4, 5, 6, or 7.
Other particular embodiments of the present invention are compounds wherein Y is NR1 completing dihydroindole ring which is
linked via the 3 position and A is a group a) which is linked via position 3:
linked via the 3 position and A is a group a) which is linked via position 2;
linked via the 3 position and A is a group b);
linked via the 3 position and A is a group c) which is linked via position 4, 3, 6, or 7;
linked via the 2 position and A is a group a) which is linked via position 3;
linked via the 2 position and A is a group a) which is linked via position 2;
linked via the 2 position and A is a group b); or
linked via the 2 position and A is a group c) which is linked via position 4, 5, 6, or 7.
Still other particular embodiments of the present invention are compounds wherein Y is N completing dihydroindole and
A is a group a) which is linked via position 3;
A is a group a) which is linked via position 2;
A is a group b); or
A is a group c) which is linked via position 4, 5, 6, or 7.
In one group of compounds W is a bond, n+m is 1 to 4, or n+m is selected from 1 and/or 2. Other groups of compounds are compounds wherein W is a bond n+m is 2 to 6, 2 to 5, 2 to 4, 3 to 6, 3 to 5, or 3 to 4.
When W is not a bond it is O, or CO.
Three further group of compounds are the compounds wherein X is CH, X is C, and X is N respectively.
R1 is in a particular embodiment selected from hydrogen, C1-6-alkyl, formyl, C1-6-alkylcarbonyl, C1-6-alkoxycarbonyl or C1-6-alkylaminocarbonyl.
In on embodiment of the invention R2 to R5 are independently selected from hydrogen, halogen, cyano, nitro, C1-6-alkyl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C1-6 alkylsulfonyl, one of R2 to R5 alternatively being a group xe2x80x94NR13R14 wherein R13 is hydrogen, C1-6-alkyl, acyl, C1-2-alkylsulfonyl, or a group xe2x80x94R16R17NCO wherein R16 is hydrogen, C1-6-alkyl, C3-8-cycloalkyl, or C3-8-cycloalkyl-C1-6-alkyl, and R17 is hydrogen or C1-6-alkyl, or R16 and R17 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, or perhydroazepin group and R14 is hydrogen or C1-6-alkyl, or R13 and R14 are linked together to form pyrrolidinyl, piperidinyl, perhydroazepin or a 5 to 7 membered unsubstituted lactam ring, in particlular R2 to R5 is selected from hydrogen, halogen, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, trifluoromethyl, and trifluoromethylsulfonyloxy.
In one group of compounds according to the invention none of R2-R5 is a group NR13R14, and in another group of compounds according to the invention at least one of R2-R5 is a group NR13R14, wherein R13 is preferably selected from methyl, formyl, acetyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, pyrrolidinylcarbonyl or 4-fluorophenylaminocarbonyl and R14 is preferably selected from hydrogen or C1-6-alkyl.
Another particular group of compounds according to the invention are compounds wherein two adjacent groups taken from R2 to R5 are joined and designate xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94, thereby forming a fused 5 membered ring.
In one embodiment of the invention R6 to R9 are independently selected from hydrogen, halogen, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, trifluoromethyl, and C1-6 alkylsulfonyl, or two adjacent groups taken from R6-R9 may be joined and designate a methylenedioxy group, in particular R6 to R9 are independently selected from hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, or two adjacent groups taken from R6-R9 may be joined and designate a methylenedioxy group.
A subgroup of compounds are the compounds wherein at least one of R8 and R9 is hydrogen and R6 to R7 are independently hydrogen or halogen, in particular chloro.
Specific examples of R11 and R12 are hydrogen or C1-6-alkyl, and R10 is hydrogen, C1-6-alkyl, or acyl.
Preferred compounds are compounds selected from
6-Chloro-3-[1-(6-bromo-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(1-Indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(1-Indanylmethyl)piperindin-4-yl]-1H-indole,
6-Chloro-3-[1-(7-methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(6-Methoxyindan-1-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, oxalate,
6-Chloro-3-[1-(6-cyano-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-(6-cyano-1-indanylmethyl)piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-(4-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-(5-acetylamino-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-(6-bromo-1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(indane-1-yl)ethyl]-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,
5-Fluoro-3-[1-[2-(indan-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Fluoro-3-[1-[2-(indan-1-yl)ethyl]-piperidin-4-yl]-1H-indole,
5-Fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Fluoro-3-[1-[4-(indan-1-yl)butan-1-yl]-piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(indan-1-yl)butan-1-yl]-piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(indan-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(indane-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl-1H-indole,
6-Chloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
7-Chloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6,7-Dichloro-3-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,
5-[4-(Indan-2-yl)methylpiperazin-1-yl]-1H-indole,
6-Chloro-3-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(indan-2-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(indan-2-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(4-(2-Propyl)oxyindan-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
4-[4-(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-1,4,5,6-tetrahydrocyclopent[e]indole,
6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole,
6-Chloro-3-[1-(4-acetylaminoindan-2-yl)methylpiperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(6-acetylaminoindan-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(6-acetylaminoindan-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(6-acetylaminoindan-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-(5-Acetylaminoindan-2-yl)methyl-1,2,3,6-tetrahydropyridine-4-yl]-6-chloro-1H-indole,
3-[1-(5-Acetylaminoindan-2-yl)methylpiperid-4-yl-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-6-chloro-1H-indole,
6-Chloro-3-[1-[2-(1-formyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(1-formyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-1H-indole,
3-[1-[2-(1-Acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-7-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6,7-dichloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5,6-methylenedioxy-1H-indole,
3-[1-[2-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
5-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,
3-[1-[3-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)propan-1-y]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-5-methyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
6-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,
3-[1-(Indan-2-ylmethyl)piperidin-4-yl]-1H-indole,
7-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,
6,7-Dichloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole,
3-[1-(Indan-2-ylmethyl)piperidin-4-yl]-5,6-methylenedioxy-1H-indole,
6-Chloro-3-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(indan-2-yl)propan-3-yl]piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(indan-2-yl)butan-4-yl]piperidin-4-yl]-1H-indole,
4-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,
5-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,
5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
1-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
2-[1-[2-(Indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Chloro-1-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,
1-[1-[2-(Indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(2,3-dihydro-1H-indol-3-yl)butyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
(+)-(3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
(xe2x88x92)-(3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[4-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)butyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
6-Chloro-3-[1-[6-chloro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[6-nitro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[6-fluoro-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[5-chloro-1-indanylmethyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[6-methyl-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-(1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-methyl-1H-indole,
6-Chloro-3-[1-(1-indanylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-(2-propyl-1H-indole,
5-Fluoro-3-[1-[6-(trifluoromethyl)-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Fluoro-3-[1-[5-(trifluoromethylsulfonyloxy)-1-indanylmethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-(1-indanylmethyloxyethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Fluoro-3-[1-[6-(indan-1-yl)hexan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-6-chloro-1H-indole,
6-Chloro-3-[1-[2-(1-formyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1-methylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1-mesylaminocarbonyl-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
3-[1-[(1-Acetyl-2,3-dihydro-1H-indol-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(1-Acetyl-2,3-dihydro-1H-indol-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-2-yl)ethyl]piperidin-4-yl]-6-chloro-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(5-fluoro-2,3-dihydro-1H-indol-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-2-[4-[(indan-2-yl)methylpiperazin-1-yl]-1H-indole,
6-Chloro-2-[4-[2-(indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,
2-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,
2-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,
6-Chloro-3-[4-[(indan-2-yl)methyl]piperazin-1-yl]-1H-indole,
6-Chloro-3-[4-[2-(indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,
3-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,
3-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-6-chloro-1H-indole,
4-[4-[(Indan-2-yl)methyl]piperazin-1-yl]-1H-indole,
4-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,
4-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol -3-yl)ethyl]piperazin-1-yl]-1H-indole,
7-[4-[(Indan-2-yl)methyl]piperazin-1-yl]-1H-indole,
7-[4-[2-(Indan-2-yl)ethyl]piperazin-1-yl]-1H-indole,
7-[4-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,
7-[4-[2-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)ethyl]piperazin-1-yl]-1H-indole,
2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5-chloro-1H-indole,
2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-1H-indole,
2-[1-[2-(1-Acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]piperidin-4-yl]-5-chloro-1H-indole,
2-[1-(Indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Chloro-2-[1-(indan-2-yl)methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
5-Chloro-2-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
2-[1-(Indan-2-yl)methylpiperidin-4-yl]-1H-indole,
5-Chloro-2-[1-(indan-2-yl)methylpiperidin-4-yl]-1H-indole,
2-[1-[2-(Indan-2-yl)ethyl]piperidin-4-yl]-1H-indole,
5-Chloro-2-[1-[2-(indan-2-yl)ethyl]piperidin-4-yl-1H-indole,
7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-3,6,7,8-tetrahydrocyclopent[e]indole,
7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-1,5,6,7-tetrahydrocyclopent[f]indole,
6-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-1,6,7,8-tetrahydrocyclopent[g]indole,
7-[4-[(6-Chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyrid-1-yl]methyl]-1,6,7,8-tetrahydrocyclopent[g]indole,
(+)6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]piperidin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)propan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[4-(2,3-dihydro-1H-indol-1-yl)butan-1-yl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole,
6-Chloro-3-[1-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropan-1-yl]-1,2,3,6-tetrahydopyrid-4-yl]-1H-indole,
3-[1-[(5-(2-Propyl)oxyindan-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[(5,6-Dimethoxyindan-2-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[(4-(2-Propyl)oxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[(5-(2-Propyl)oxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[(7-Methoxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-(5,6-Dimethoxyindan-1-yl)methyl]piperidin-4-yl]-6-chloro-1H-indole,
3-[1-[(4-(2-Propyl)oxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(5-(2-Propyl)oxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(5,6-Dimethoxyindan-2-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(4-(2-Propyl)oxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(5-(2-Propyl)oxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(7-Methoxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole,
3-[1-[(5,6-Dimethoxyindan-1-yl)methyl]-1,2,3,6-tetrahydropyridin-4-yl]-6-chloro-1H-indole, or
3-[4-[(5,6-Dimethoxyindan-1-yl)methyl]-piperazin-1-yl]-6-chloro-1H-indole,
and pharmaceutically acceptable acid addition salts thereof.
The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The compounds of the invention may be prepared as follows:
1) Alkylating a piperazine, piperidine, or tetrahydropyridine of the formula II with an alkylating derivative of the formula III: 
wherein R2-R5, X, Y, A, n, m, W, and the dotted line are as previously defined, and L is a leaving group such as eg. halogen, mesylate, or tosylate;
2) Reducing the amide carbonyl in a compound of the following Formula IV: 
wherein R2-R5, X, Y, A, m, W and the dotted line are as previously defined and r is nxe2x88x921 and n is as defined above;
3) Introducing a substituent R2xe2x80x2, R3xe2x80x2, R4xe2x80x2 or R5xe2x80x2 by reacting a compound of the following Formula V: 
wherein one of R2xe2x80x2-R5xe2x80x2 is hydrogen and the others are the corresponding R2, R3, R4, or R5 as previously defined and X, Y, A, m, n, W, and the dotted line are as previously defined, by using a reactive reagent such as a halogen or a halogenating agent, a sulfonating agent, a nitration agent or a reactive agent generating carbonium ions (RCO+, R+) wherein R is alkyl alkynyl, aryl cycloalkyl, or cycloalk(en/yn)yl;
4) Reducing the double bond in an indole compound of the following Formula VI: 
wherein R2-R5, R1, X, n, m, W, and A are as previously defined;
5) Reducing the tetrahydropyridinyl double bond in derivatives of the following Formula VII 
wherein R2-R5, Y, n, m, W, and A are as previously defined;
6) Reacting a dihydroindole derivative of formula VIII: 
wherein R2-R5, X, A, n, m, W, and the dotted line are as previously defined, with a reagent of the formula R1-L, where L is a leaving group such as halogen, mesylate or tosylate and R1 is as previously defined, or of the formula R1xe2x80x2-hal or R1xe2x80x2-OCOR, in which formulas hal is halogen, R1xe2x80x2 is acyl, thioacyl, a group R15VCOxe2x80x94, or a group R16R17NCOxe2x80x94 or R16R17NCSxe2x80x94 where R15, V, R16 and R17 are as previously defined except that neither R16 nor R17 may be hydrogen, or with a lower alkylsulfonyl halogenide, trifluoromethylsulhonyl halogenide or an isocyanate or thioisocyanate of the formula R16xe2x80x94Nxe2x95x90Cxe2x95x90O or R16xe2x80x94Nxe2x95x90Cxe2x95x90S wherein R16 is as previously defined;
7) Reacting an anilino derivative of the formula IX: 
wherein one of R2-R5 is NHR14, and R14 is defined as above and the other R2-R5, X, Y, A, n, m, W, and the dotted line are as previously defined, with a reagent of the formula R13-L, where L is a leaving group such as halogen, mesylate or tosylate and R13 is as previously defined, or of the formula R13xe2x80x2-hal or R13xe2x80x2-OCOR, in which formulas hal is halogen, R13xe2x80x2 is acyl, thioacyl, a group R15VCOxe2x80x94, or a group R16R17NCOxe2x80x94 or R16R17NCSxe2x80x94 where R15, V, R16 and R17 are as previously defined except that neither R16 nor R17 may be hydrogen, or with a lower alkylsulfonyl halogenide, trifluoromethylsulhonyl halogenide or an isocyanate or thioisocyanate of the formula R16xe2x80x94Nxe2x95x90Cxe2x95x90O or R16xe2x80x94Nxe2x95x90Cxe2x95x90S wherein R16 is as previously defined;
8) Alkylating a dihydroindole derivative of the Formula X with an alkylating derivative of the Formula XI: 
wherein R2-R5, X, A, n, m, W, and the dotted line are as previously defined, and L is a leaving group such as eg. halogen, mesylate, or tosylate; or
9) reducing the carbonyl amide compounds of Formula XII: 
wherein R2-R5, X, A, n, W and the dotted line are as previously defined and s is mxe2x88x921 and m is as defined above; whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The reaction in Methods 6) and 7) are conveniently performed at low temperature (eg. below room temperature) in an inert solvent such as acetone, dichloromethane, tetrahydrofuran or dimethoxyethane when reactive carboxylic acid chlorides, isocyanates, or isothiocyanates are used. Formylated amines are prepared from the corresponding amines by reaction in formic acid, with esters of formic acid, or by reaction with mixed formic acid anhydride prepared in situ. Generally, reaction temperatures are between 0xc2x0 C. and the boiling point of the formyl precursor compounds.
The alkylations according to Methods 1) and 8) are generally performed by refluxing in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in the presence of a base such as triethylamine or potassium carbonate.
The reductions of double bonds according to Methods 4) and 5) are generally performed by catalytic hydrogenation at low pressure ( less than 3 atm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran, dioxane, or diethyl ether.
The reductions according to Methods 2) and 9) are generally performed by use of LiAlH4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature.
The halogenation according to Method 3) is generally performed by use of chlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide or another halogen precursor molecule, conveniently in the presence of a catalyst such as Fe ions or a mineral acid.
The indoles 7-chloro-1H-indole and 6,7-dichloro-1H-indole were prepared in accordance with the procedure of G. Bartoli et al., Tetrahedron Lett. 1989, 30, 2129-2132. The two piperazinylindoles 4-(piperazin-1-yl)-1H-indole and 5-(piperazin-1-yl)-1H-indole have been described in the literature, WO patent publication No. 95/33743 and U.S. Pat. No. 5,576,319.
Synthesis of 3-(piperidin-4-yl)-1H-indoles and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles have been described in the literature EP-A1-465398.
Key intermediates such as 1-indanecarboxylic acid (V. Asham and W. H. Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al. Helv.Chim.Acta 1982, 33, 325-343) and 6-nitro-1-indanecarboxylic acid (G. Kirsch et al. Just. Lieb. Ann. Chem. 1976, 10, 1914) were prepared according to well-known literature procedures. (Indan-2-yl)acetic acid, 3-(indan-2-yl)propionic acid, 4-(indan-2-yl)butyric acid, and 2-(indan-2-yl)ethanol have been described in the literature (Y. Tanaka et al. J. Med. Chem. 1994, 37, 2071-2078).